Substituted phenol compounds useful for anesthesia and sedation

ABSTRACT

The invention provides substituted phenol compounds and pharmaceutical compositions containing substituted phenol compounds which are useful for inducing or maintaining anesthesia or sedation in a mammal. This invention also provides methods for inducing or maintaining anesthesia or sedation in a mammal using substituted phenol compounds.

CROSS-REFERENCE TO RELATED APPLICATIONS

This application is a continuation of U.S. application Ser. No.10/255,889, filed on Sep. 26, 2002, now U.S. Pat. No. 6,815,555 B2,which claims the benefit of U.S. Provisional Application No. 60/325,044,filed on Sep. 26, 2001; the entire disclosures of which are incorporatedherein by reference in their entirety.

FIELD OF THE INVENTION

This invention is directed to substituted phenol compounds;pharmaceutical compositions containing substituted phenol compounds; andmethods of using such compounds and compositions to induce or maintaingeneral anesthesia or sedation in a mammal. This invention is alsodirected to processes and intermediates useful for preparing substitutedphenol compounds.

BACKGROUND OF THE INVENTION

Propofol (i.e., 2,6-diisopropylphenol) is an injectable anesthetic usedto induce and maintain general anesthesia and sedation. Because of itsbeneficial properties and ease of administration, propofol iswidely-used for both human and veterinary applications.

One drawback of propofol is that it is retained in the body andmetabolized relatively slowly. Therefore, patient recovery can beunpredictable and is often dependent on the total amount of propofoladministered.

Accordingly, a need exists for novel anesthetic agents. In particular, aneed exists for novel anesthetic agents having a predictable duration ofaction.

SUMMARY OF THE INVENTION

The present invention provides substituted phenol compounds andpharmaceutical compositions containing substituted phenol compounds,which compounds and compositions are useful for inducing and maintaininggeneral anesthesia or sedation in a mammal. The substituted phenolcompounds of this invention contain a reactive functional group whichallows the compounds to be converted (i.e., hydrolyzed or metabolized)in vivo into an inactive derivative. Thus, the substituted phenolcompounds of this invention have a predictable duration of action whenadministered to a patient.

Accordingly, in one of its composition aspects, this invention providesa pharmaceutical composition comprising a pharmaceutically acceptablecarrier and a compound selected from the group consisting of:

wherein

R₁ and R₂ are each independently (C₁–C₈)alkyl, (C₃–C₈)cycloalkyl, or(C₃–C₈)cycloalkyl(C₁–C₈)alkyl;

L is selected from the group consisting of covalent bond and ahydrocarbylene group containing from 1 to about 12 carbon atoms andoptionally containing from 1 to about 5 heteroatoms selected from thegroup consisting of oxygen, nitrogen, and sulfur; and

R₃ is selected from the group consisting of —C(═O)OR_(a), —C(═O)SR_(a),—P(═O)(OR_(a))₂, —C(═O)OCH₂C(═O)N(R_(a))₂, and —C(═O)OC(═O)R_(a) whereineach R_(a) is independently selected from a hydrocarbyl group containingfrom 1 to about 20 carbon atoms and optionally containing from 1 toabout 5 heteroatoms selected from the group consisting of halo,nitrogen, oxygen and sulfur;

or a pharmaceutically acceptable salt thereof.

In another of its composition aspects, this invention provides acompound of formula (V):

wherein L is a covalent bond, methylene, or ethylene; and R₃ is asdefined herein;

provided when L is a covalent bond, R₃ is not —C(═O)OR_(a) wherein R_(a)is methyl, ethyl, 1,2-dibromoethyl, but-2-enyl, hexadecyl, stearyl, orbenzyl; and

provided when L is ethylene, R₃ is not —C(═O)OR_(a) wherein R_(a) ismethyl or stearyl;

or a pharmaceutically acceptable salt thereof.

In yet another of its composition aspects, this invention provides acompound of formula (X):

wherein

R₄ is (C₁–C₅)alkyl, (C₂–C₅)alkenyl, or (C₂–C₅)alkynyl;

R₅ is (C₁–C₆)alkyl, (C₃–C₈)cycloalkyl, or (C₃–C₈)cycloalkyl(C₁–C₆)alkyl;and

R₆ is methyl;

or R₅ and R₆ together with the carbon atom to which they are attachedform a (C₃₋₈)cycloalkyl; and

R_(a) is (C₁–C₈)alkyl, (C₂–C₈)alkenyl, (C₂–C₈)alkynyl, or(C₃–C₈)cycloalkyl.

The substituted phenol compounds and pharmaceutical compositions of thisinvention are useful for inducing or maintaining anesthesia or sedationin a mammal, such as a human or domesticated mammal.

Accordingly, in one of its method aspects, this invention is directed toa method for inducing or maintaining anesthesia or sedation in a mammal,comprising administering to a mammal an anesthesia or sedation-producingamount of a pharmaceutical composition comprising a pharmaceuticallyacceptable carrier and a compound selected from formulae (I) or (II), ora pharmaceutically acceptable salt thereof.

The invention also provides substituted phenol compounds for use inmedical therapy (e.g. for inducing or maintaining anesthesia orsedation). Additionally, this invention provides substituted phenolcompounds for use in the manufacture of a medicament useful for inducingor maintaining anesthesia or sedation in a mammal (e.g. a human).

The invention also provides processes and intermediates disclosed hereinthat are useful for preparing substituted phenol compounds, or that areuseful for preparing compositions comprising substituted phenolcompounds.

DETAILED DESCRIPTION

When describing the compounds, compositions and methods of thisinvention, the following terms have the following meaning unlessotherwise indicated: halo is fluoro, chloro, bromo, or iodo. Alkyl,alkoxy, alkenyl, alkynyl, etc. denote both straight and branched groups;but reference to an individual radical such as “propyl” embraces onlythe straight chain radical, a branched chain isomer such as “isopropyl”being specifically referred to. Aryl denotes a phenyl radical or anortho-fused bicyclic carbocyclic radical having about nine to ten ringatoms in which at least one ring is aromatic.

The term “hypnotic agent” refers generally to a compound that promotessleep or is used to induce or maintain anesthesia or sedation.

The term “anesthesia” as used herein refers to a loss of sensationresulting from pharmacologic depression of nerve function.

The term “sedation” is defined herein as the calming of mentalexcitement or abatement of physiological function by administration of adrug.

The term “effective amount” refers to that amount which is sufficient toinduce or maintain anesthesia or sedation when administered to a mammal;i.e., an anesthesia- or sedation-producing amount. This amount will varydepending on the subject and the manner of administration, and can bedetermined routinely by one of ordinary skill in the art.

The term “analgesic” refers to a compound that relieves pain by alteringperception of nociceptive stimuli without producing significantanesthesia or loss of consciousness.

The term “opioid” refers to-synthetic narcotics that have opiate-likeactivities (e.g., induction of sleep).

The term “linking group,” identified by the symbol L, refers to ahydrocarbylene group which links the phenol ring to the reactivefunctional group in the substituted phenol compounds of this invention.Preferably, the linking group is a covalent bond or a hydrocarbylenegroup containing from about 1 to about 12 carbon atoms and optionallycontaining from 1 to about 5 heteroatoms selected from the groupconsisting of oxygen, nitrogen and sulfur. Typically, a linking groupseparates the reactive functional group (e.g. R₃) from the phenol ringby about 5 to about 100 angstroms, or preferably by about 5 to about 20angstroms. Suitable linking groups include divalent alkylene,alkenylene, and alkynylene chains. In addition, the linker canincorporate ether or thioether groups within the chain; the linkinggroup can also be linked to the reactive functional group or to thephenol ring through ether or thioether groups.

The term “reactive functional group,” identified by the symbol R₃,refers to a functional group which is converted (e.g. hydrolyzed ormetablized) in vivo to a functional group which renders the resultingcompound essentially inactive as an anesthetic or sedative agent invivo. The term reactive functional group includes, by way ofillustration, carboxylic acid esters and thioesters; phosphonic acidesters and thioesters; carboxylic acid anhydrides and the like; whichare converted in vivo to provide the corresponding carboxylic orphosphonic acid.

The term reactive functional group also includes other hydrophobicgroups that are degraded enzymatically in vivo to provide a group thatdeactivates the substituted phenol compound (e.g. by preventing theresulting derivative from crossing the blood-brain barrier) and/or thatprovide a derivative that is essentially inactive in vivo.

The reactive functional group can be linked directly to any carbon atomof the phenol ring by a covalent bond. Alternatively, the reactivefunctional group can be linked to the phenol ring through a linker,which can be attached to any carbon atom of the phenol ring by acovalent bond.

The term “hydrocarbyl” refers to a monovalent organic radical composedprimarily of carbon and hydrogen and which may optionally contain 1 toabout 5 heteroatoms selected from the group consisting of halo,nitrogen, oxygen and sulfur. Such hydrocarbyl groups may be aliphatic,alicyclic, aromatic or combinations thereof (e.g. aralkyl or alkaryl)and include, by way of illustration, groups such as alkyl, alkenyl,alkynyl, cycloalkyl, cycloalkenyl, aryl, aralkyl and alkaryl groups.

The term “hydrocarbylene” refers to a divalent organic radical composedprimarily of carbon and hydrogen and which may optionally contain 1 toabout 5 heteroatoms selected from the group consisting of halo,nitrogen, oxygen and sulfur. Such hydrocarbylene groups may bealiphatic, alicyclic, aromatic or combinations thereof (e.g. aralkyleneor alkarylene) and include, by way of illustration, groups such asalkylene, alkenylene, alkynylene, arylene, aralkylene and alkarylenegroups.

The term “carboxylic acid ester” refers to a group of the formula—C(O)OR, where R is a hydrocarbyl group containing from about 1 to about12 carbon atoms and optionally containing 1 to about 5 heteroatomsselected from the group consisting of halo, nitrogen, oxygen and sulfur.Representative carboxylic acid ester groups include, for example,methoxycarbonyl, ethoxycarbonyl, isopropoxycarbonyl, phenoxycarbonyl,benzyloxycarbonyl, and the like.

The term “carboxylic acid thioester” refers to a group of the formula—C(O)SR, where R is a hydrocarbyl group containing from about 1 to about12 carbon atoms and optionally containing 1 to about 5 heteroatomsselected from the group consisting of halo, nitrogen, oxygen and sulfur.Representative carboxylic acid thioester groups include, for example,thiomethoxycarbonyl, thioethoxycarbonyl, and the like.

The term “phosphonic acid ester” refers to a group of the formula—P(O)(OR)₂, where each R is independently a hydrocarbyl group containingfrom about 1 to about 12 carbon atoms and optionally containing 1 toabout 5 heteroatoms selected from the group consisting of halo,nitrogen, oxygen and sulfur. Representative phosphonic acid ester groupsinclude, for example, dimethoxyphosphono, diethoxyphosphono,diphenoxyphosphono, dibenzyloxyphosphono, and the like.

The term “phosphonic acid thioester” refers to a group of the formula—P(O)(SR)₂, where each R is independently a hydrocarbyl group containingfrom about 1 to about 12 carbon atoms and optionally containing 1 toabout 5 heteroatoms selected from the group consisting of halo,nitrogen, oxygen and sulfur. Representative phosphonic acid thioestergroups include, for example, dithiomethoxyphosphono,dithioethoxyphosphono, and the like.

The term “carboxylic acid anhydride” refers to a group of the formula—C(O)OC(O)R, where R is a hydrocarbyl group containing from about 1 toabout 12 carbon atoms and optionally containing 1 to about 5 heteroatomsselected from the group consisting of halo, nitrogen, oxygen and sulfur.Representative carboxylic acid anhydride groups include, for example,(tert-butylcarbonyloxy)carbonyl, and the like.

It will be appreciated by those skilled in the art that compounds havinga chiral center may exist in and be isolated in optically active andracemic forms. Some compounds may exhibit polymorphism. It is to beunderstood that the present invention encompasses any racemic,optically-active, polymorphic, or stereoisomeric form, or mixturesthereof, of a compound of the invention, which possesses the usefulproperties described herein, it being well known in the art how toprepare optically active forms (for example, by resolution of theracemic form by recrystallization techniques, by synthesis fromoptically-active starting materials, by chiral synthesis, or bychromatographic separation using a chiral stationary phase).

For any group described herein that can be optionally substituted, it isunderstood that such groups do not contain any substitution orsubstitution patterns which are sterically impractical and/orsynthetically non-feasible.

While a broad definition of the invention is set forth in the Summary ofthe Invention, certain compounds or compositions may be preferred.Specific and preferred values listed herein for radicals, substituents,and ranges, are for illustration only; they do not exclude other definedvalues or other values within defined ranges for the radicals andsubstituents.

In one embodiment, a compound that can be incorporated into thepharmaceutical compositions of the invention and that can beadministered according to the methods of the invention is a compound ofFormula (I):

wherein L and R₃ are as defined herein; and R₁ is (C₁–C₈)alkyl,(C₃–C₈)cycloalkyl, or (C₃–C₈)cycloalkyl(C₁–C₈)alkyl.

In another embodiment, a compound that can be incorporated into thepharmaceutical compositions of the invention and that can beadministered according to the methods of the invention is a compound offormula (II):

wherein L and R₃ are as defined herein; and R₁ and R₂ are eachindependently (C₁–C₈)alkyl, (C₃–C₈)cycloalkyl, or(C₃–C₈)cycloalkyl(C₁–C₈)alkyl.

In another embodiment, a compound that can be incorporated into thepharmaceutical compositions of the invention and that can beadministered according to the methods of the invention is a compound offormula (III):

wherein y is 0, 1, 2, 3, 4, 5, or 6; and R₃ is as defined herein.

Another compound that can be incorporated into the pharmaceuticalcompositions of the invention and that can be administered according tothe methods of the invention is a compound of formula (IV):

wherein y is 0, 1, 2, 3, 4, 5, or 6; and R₃ is as defined herein.

Specifically, (C₁–C₈)alkyl can be methyl, ethyl, propyl, isopropyl,butyl, iso-butyl, sec-butyl, pentyl, 2-pentyl, 3-pentyl, hexyl, 2-hexyl,heptyl, 2-heptyl, octyl, or 2-octyl; (C₃–C₈)can be cyclopropyl,cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, or cyclooctyl;(C₃–C₈)cycloalkyl(C₁–C₈)alkyl can be cyclopropylmethyl,cyclobutylmethyl, cyclopentylmethyl, cyclohexylnethyl,2-cyclopropylethyl, 2-cyclobutylethyl, 2-cyclopentylethyl, or2-cyclohexylethyl; (C₁–C₈)alkoxy can be methoxy, ethoxy, propoxy,isopropoxy, butoxy, iso-butoxy, sec-butoxy, pentoxy, 3-pentoxy,hexyloxy, heptyloxy, or oxtyloxy; (C₂–C₈)alkenyl can be vinyl, allyl,1-propenyl, 2-propenyl, 1-butenyl, 2-butenyl, 3-butenyl, 1,-pentenyl,2-pentenyl, 3-pentenyl, 4-pentenyl, 1-hexenyl, 2-hexenyl, 3-hexenyl,4-hexenyl, 2,4-hexadienyl, or 5-hexenyl, 1-heptenyl, 2-heptenyl,3-heptenyl, 4-heptenyl, 5-heptenyl, 6-heptenyl, 1-octenyl, 2-octenyl,3-octenyl, 4-octenyl, 5-octenyl, 6-octenyl, 7-octenyl; (C₂–C₈)alkynylcan be ethynyl, 1-propynyl, 2-propynyl, 1-butynyl, 2-butynyl, 3-butynyl,1-pentynyl, 2-pentynyl, 3-pentynyl, 4-pentynyl, 1-hexynyl, 2-hexynyl,3-hexynyl, 4-hexynyl, 2,4-hexadiynyl, 5-hexynyl, 1-heptynyl, 2-heptynyl,3-heptynyl, 4-heptynyl, 5-heptynyl, 6-heptynyl, 1-octynyl, 2-octynyl,3-octynyl, 4-octynyl, 5-octynyl, 6-octynyl, or 7-octynyl;(C₁–C₈)alkanoyl can be acetyl, propanoyl, butanoyl, pentanoyl, hexanoyl,heptanoyl, or octanoyl; (C₁–C₈)alkoxycarbonyl can be methoxycarbonyl,ethoxycarbonyl, propoxycarbonyl, isopropoxycarbonyl, butoxycarbonyl,pentoxycarbonyl, hexyloxycarbonyl, heptyloxycarbonyl, oroctyloxycerbonyl; (C₁–C₈)alkylene can be methylene, ethylene, propylene,isopropylene, butylene, iso-butylene, sec-butylene, pentylene,2-pentylene, 3-pentylene, hexylene, 2-hexylene, heptylene, 2-heptylene,octylene, or 2-octylene; (C₃–C₈)cycloalkylene can be cyclopropylene,cyclobutylene, cyclopentylene, cyclohexylene, cycloheptylene, orcyclooctylene; (C₂–C₈)alkenylene can be vinylene, allylene,1-propenylene, 2-propenylene, 1-butenylene, 2-butenylene, 3-butenylene,1,-pentenylene, 2-pentenylene, 3-pentenylene, 4-pentenylene,1-hexenylene, 2-hexenylene, 3-hexenylene, 4-hexenylene,2,4-hexadienylene, or 5-hexenylene, 1-heptenylene, 2-heptenylene,3-heptenylene, 4-heptenylene, 5-heptenylene, 6-heptenylene,1-octenylene, 2-octenylene, 3-octenylene, 4-octenylene, 5-octenylene,6-octenylene, 7-octenylene; (C₂–C₈)alkynylene can be ethynylene,1-propynylene, 2-propynylene, 1-butynylene, 2-butynylene, 3-butynylene,1-pentynylene, 2-pentynylene, 3-pentynylene, 4-pentynylene,1-hexynylene, 2-hexynylene, 3-hexynylene, 4-hexynylene,2,4-hexadiynylene, 5-hexynylene, 1-heptynylene, 2-heptynylene,3-heptynylene, 4-heptynylene, 5-heptynylene, 6-heptynylene,1-octynylene, 2-octynylene, 3-octynylene, 4-octynylene, 5-octynylene,6-octynylene, or 7-octynylene; and aryl can be phenyl, indenyl, ornaphthyl.

Specifically, R₁ and R₂ are each independently selected from the groupconsisting of (C₁–C₈)alkyl and (C₃–C₈)cycloalkyl.

Specifically, R₁ and R₂ are each independently selected from the groupconsisting of (C₁–C₆)alkyl and (C₃–C₆)cycloalkyl.

Preferably, R₁ and R₂ are each independently isopropyl, 2-butyl,2-pentyl, 3-pentyl, 2-hexyl, 3-hexyl, or (C₃–C₆)cycloalkyl.

Specifically, R₁ and R₂ are each independently selected from the groupconsisting of (C₂–C₄)alkyl and (C₃–C₆)cycloalkyl.

Specifically, R₁ and R₂ are each independently (C₁–C₆)alkyl.

More specifically, R₁ and R₂ are each independently selected from thegroup consisting of (C₂–C₄)alkyl.

More preferably, R₁ and R₂ are each isopropyl.

Specifically, R₃ is —C(═O)OR_(a), —C(═O)SR_(a), —P(═O)(OR_(a))₂,—C(═O)OCH₂C(═O)N(R_(a))₂, or —C(═O)OC(═O)R_(a) wherein R_(a) is(C₁–C₈)alkyl, (C₂–C₈)alkenyl, (C₂–C₈)alkynyl, (C₃–C₈)cycloalkyl,(C₃–C₈)cycloalkenyl, (C₃–C₈)cycloalkyl(C₁–C₈)alkyl,(C₃–C₈)cycloalkenyl(C₁–C₈)alkyl, aryl, aryl(C₁–C₈)alkyl,aryl(C₁–C₈)alkenyl, or aryl(C₁–C₈)alkynyl wherein any (C₁–C₈)alkyl,(C₁–C₈)alkenyl, (C₁–C₈)alkynyl, (C₃–C₈)cycloalkyl, or aryl is optionallysubstituted by one or more halo, cyano, (C₁–C₈)alkoxycarbonyl,(C₁–C₈)alkanoyl, or (C₁–C₈)alkoxy.

Specifically, R₃ is —C(═O)OR_(a), —C(═O)SR_(a), or —C(═O)OC(═O)R_(a)wherein R_(a) is (C₁–C₈)alkyl, (C₂–C₈)alkenyl, (C₂–C₈)alkynyl,(C₃–C₈)cycloalkyl, (C₃–C₈)cycloalkenyl (C₃–C₈)cycloalkyl(C₁–C₈)alkyl,(C₃–C₈)cycloalkenyl(C₁–C₈)alkyl, aryl, aryl(C₁–C₈)alkyl,aryl(C₁–C₈)alkenyl, or aryl(C₁–C₈)alkynyl wherein any (C₁–C₈)alkyl,(C₁–C₈)alkenyl, (C₁–C₈)alkynyl, (C₃–C₈)cycloalkyl, or aryl is optionallysubstituted by one or more halo, cyano, (C₁–C₈)alkoxycarbonyl,(C₁–C₈)alkanoyl, or (C₁–C₈)alkoxy.

More specifically, R₃ is —C(═O)OR_(a), —C(═O)SR_(a), or—C(═O)OC(═O)R_(a).

More specifically, R₃ is —C(═O)OR_(a).

Specifically, R_(a) is (C₁–C₈)alkyl, (C₂–C₈)alkenyl, (C₂–C₈)alkynyl,(C₃–C₈)cycloalkyl, aryl, aryl(C₁–C₈)alkyl, aryl(C₁–C₈)alkenyl, oraryl(C₁–C₈)alkynyl.

More specifically, R_(a) is (C₁–C₈)alkyl, (C₂–C₈)alkenyl,(C₂–C₈)alkynyl, or (C₃–C₈)cycloalkyl.

More specifically, R_(a) is (C₁–C₆)alkyl, (C₂–C₆)alkenyl, or(C₂–C₆)alkynyl.

More specifically, R_(a) is methyl, ethyl, propyl, isopropyl, 2-butyl,or benzyl.

Preferably, L is selected from the group consisting of a covalent bondand a hydrocarbylene group containing from about 1 to about 8 carbonatoms and optionally containing from 1 to about 5 heteroatoms selectedfrom the group consisting of oxygen, nitrogen and sulfur.

Specifically, L is a bond, (C₁–C₆)alkylene, (C₂–C₆)alkenylene, or(C₂–C₆)alkynylene.

More specifically, L is methylene, ethylene, vinylene, propylene,allylene, butylene, pentylene, or hexylene.

A preferred value for L is a covalent bond, methylene, ethylene, orvinylene.

In one embodiment, a preferred group of compounds that can beincorporated into the pharmaceutical compositions of the invention isthe group of compounds wherein R₁ and R₂ are each independently selectedfrom the group consisting of (C₁–C₈)alkyl and (C₃–C₈)cycloalkyl; R₃ is—C(═O)OR_(a), —C(═O)SR_(a), or —C(═O)OC(═O)R_(a) wherein R_(a) is(C₁–C₈)alkyl, (C₂–C₈)alkenyl, (C₂–C₈)alkynyl, (C₃–C₈)cycloalkyl, aryl,aryl(C₁–C₈)alkyl, aryl(C₁–C₈)alkenyl, or aryl(C₁–C₈)alkynyl; and L is acovalent bond, (C₁–C₆)alkylene, (C₂–C₆)alkenylene, or (C₂–C₆)alkynylene.

In another embodiment, a preferred group of compounds is the group ofcompounds wherein R₁ and R₂ are each independently isopropyl, 2-butyl,2-pentyl, 3-pentyl, 2-hexyl, 3-hexyl, or (C₃–C₆)cycloalkyl; R₃ is—C(═O)OR_(a) wherein R_(a) is (C₁–C₈)alkyl, (C₂–C₈)alkenyl,(C₂–C₈)alkynyl, (C₃–C₈)cycloalkyl, aryl, aryl(C₁–C₈)alkyl,aryl(C₁–C₈)alkenyl, or aryl(C₁–C₈)alkynyl; and L is methylene, ethylene,vinylene, propylene, allylene, butylene, pentylene, or hexylene.

A preferred group of compounds of formula (I) is the group of compoundswherein the group -L-R₃ is attached to the phenyl ring of formula (I) atthe position ortho to the hydroxy group.

Another preferred group of compounds of formula (I) is the group ofcompounds wherein the group -L-R₃ is attached to the phenyl ring offormula (I) at the position para to the hydroxy group.

A preferred group of compounds of formula (II) is the group of compoundswherein the group -L-R₃ is attached to the phenyl ring of formula (II)at the position para to the hydroxy group.

A preferred group of compounds of formula (III) is the group ofcompounds wherein R₃ is —C(═O)OR_(a).

The invention also provides a compound of formula (X):

wherein

R₄ is (C₁–C₅)alkyl, (C₂–C₅)alkenyl, or (C₂–C₅)alkynyl;

R₅ is (C₁–C₆)alkyl, (C₃–C₈)cycloalkyl, or (C₃–C₈)cycloalkyl(C₁–C₆)alkyl;and

R₆ is methyl;

or R₅ and R₆ together with the carbon atom to which they are attachedform a (C₃–C₈)cycloalkyl; and

R_(a) is (C₁–C₈)alkyl, (C₂–C₈)alkenyl, (C₂–C₈)alkynyl or(C₃–C₈)cycloalkyl.

A preferred group of compounds of formula (X) is the group of compoundswherein R₄ is selected from (C₁–C₅)alkyl; and R₅ is selected from(C₁–C₅)alkyl; or R₅ and R₆ together with the carbon atom to which theyare attached form a (C₃–C₆)cycloalkyl; and R_(a) is (C₁–C₈)alkyl.

A preferred group of compounds of formula (X) is the group of compoundswherein R₄ is methyl or ethyl; and R₅ is independently methyl or ethyl;or R₅ and R₆ together with the carbon atom to which they are attachedform a (C₃₋₆)cycloalkyl; and R_(a) is ethyl, propyl, isopropyl or2-butyl.

Another preferred group of compounds of formula (X) is the group ofcompounds wherein R₄ and R₅ together with the carbon atom to which theyare attached form a (C₃–C₆)cycloalkyl.

Preferred compounds of formula (X) include the following:

-   6-isopropyl-2-(1-ethoxycarbonylethyl)-phenol;-   6-isopropyl-2-(1-propoxycarbonylethyl)-phenol;-   6-isopropyl-2-(2-propoxycarbonylethyl)-phenol;-   6-isopropyl-2-(1 -ethoxycarbonyl-2-propyl)-phenol-   6-isopropyl-2-(1-propoxycarbonyl-2-propyl)-phenol;-   6-isopropyl-2-(2-propoxycarbonyl-2-propyl)-phenol;-   6-(2-butyl)-2-(1-ethoxycarbonylpropyl)-phenol;-   6-(2-butyl)-2-(1-propoxycarbonylpropyl)-phenol;-   6-(2-butyl)-2-(2-propoxycarbonylpropyl)-phenol;-   6-(2-butyl)-2-(1-ethoxycarbonylethyl)-phenol;-   6-(2-butyl)-2-(1-propoxycarbonylethyl)-phenol; and-   6-(2-butyl)-2-(2-propoxycarbonylethyl)-phenol.

Another preferred group of compounds of formula (I) that can beincorporated in the pharmaceutical compositions of the invention is thegroup of compounds of formula (X).

Processes for preparing the compounds described herein are provided asfurther embodiments of the invention and are illustrated by thefollowing procedures in which the meanings of the generic radicals areas given above unless otherwise qualified. Accordingly, the inventionprovides a method for preparing a phenol of formula (II) wherein L is acovalent bond and R₃ is a 4-methoxycarbonyl group, comprising treating acorresponding phenol wherein -L-R₃ is absent with carbontetrachlorideand a copper catalyst in the presence of methanol and an suitable base(e.g., NaOH), for example, as described in example 1. The invention alsoprovides a method for preparing a compound of formula (I, II, III, orIV), comprising deprotecting a corresponding protected phenol of formula(VI, VII, VIII, or IX) wherein R_(x) is a suitable protecting group(such as for example methyl, benzyl or acetate), for example, asdescribed in examples 2 and 3.

An intermediate useful for preparing a compound of formula (I) is acorresponding protected ether of formula (VI):

wherein R₁, L, and R₃ have any of the values, specific values orpreferred values described herein; and wherein R_(x) is a suitableprotecting group (e.g. methyl, benzyl or acetate). Suitable hydroxyprotecting groups are well known in the art, for example, see Greene, T.W.; Wutz, P. G. M. “Protecting Groups In Organic Synthesis” secondedition, 1991, New York, John Wiley & sons, Inc.

Another intermediate useful for preparing a compound of formula (II) isa corresponding protected ether of formula (VII):

wherein R₁, R₂, L, and R₃ have any of the values, specific values orpreferred values described herein; and wherein R_(x) is a suitableprotecting group (e.g. methyl, benzyl or acetate).

An intermediate useful for preparing a compound of formula (III) is acorresponding protected ether of formula (VIII):

wherein R₃ has any of the values, specific values or preferred valuesdescribed herein; y is 0, 1, 2, 3, 4, 5, or 6; and wherein R_(x) is asuitable protecting group (e.g. methyl or benzyl).

An intermediate useful for preparing a compound of formula (IV) is acorresponding protected ether of formula (IX):

wherein R₃ has any of the values, specific values or preferred valuesdescribed herein; y is 0, 1, 2, 3, 4, 5, or 6; and wherein R_(x) is asuitable protecting group (e.g. methyl or benzyl).

An intermediate useful for preparing a compound of formula (X) is acorresponding benzofuran of formula (A):

wherein R₄ and R₅ have any of the values, specific values or preferredvalues described herein.

Another intermediate useful for preparing a compound of formula (X) is acompound of formula (B):

wherein R₄, R₅, and R_(a) have any of the values, specific values orpreferred values described herein.

In cases where active compounds are sufficiently basic or acidic to formstable nontoxic acid or base salts, administration of the compounds assalts can be appropriate. Examples of pharmaceutically acceptable saltsare organic acid addition salts formed with acids which form aphysiological acceptable anion, for example, tosylate, methanesulfonate,acetate, citrate, malonate, tartarate, succinate, benzoate, ascorbate,α-ketoglutarate, and α-glycerophosphate. Suitable inorganic salts canalso be formed, including chloride, sulfate, nitrate, bicarbonate, andcarbonate salts.

Pharmaceutically acceptable salts can be obtained using standardprocedures well known in the art, for example by reacting a sufficientlybasic compound such as an amine with a suitable acid affording aphysiologically acceptable anion. Alkali metal (for example, sodium,potassium or lithium) or alkaline earth metal (for example calcium)salts of carboxylic acids can also be made.

The compounds of formulae (I) and (II) can be formulated aspharmaceutical compositions and administered to a mammalian host, suchas a human patient in a variety of forms adapted to the chosen route ofadministration, i.e., parenterally, by intravenous, intramuscular,topical or subcutaneous routes; or orally.

Active compounds described herein are typically formulated aspharmaceutical compositions which are suitable for intravenousadministration. Like propofol, the active compounds described herein arerelatively insoluble in water. Thus, for intravenous administration, thecompounds of the invention are typically formulated in aqueous mediausing water-immiscible solvents, solubilizers, emulsifiers, surfactantsor other solubilizing agents. Some emulsifiers are variously termedsurfactants in the literature. Individual formulations may include oneor more additional components such as stabilizers, tonicity modifiers,bases or acids to adjust pH, and solubilizers. The formulations can alsooptionally contain a preservative, such as ethylenediaminetetraaceticacid (EDTA) or sodium metabisulfate, to prevent the growth ofmicroorganisms. Of course, any material used in preparing any unitdosage form should be pharmaceutically acceptable and substantiallynon-toxic in the amounts employed.

A wide range of water-immiscible solvents can be used in thecompositions of the present invention. The water-immiscible solvent canbe a vegetable oil, for example soybean, safflower, cottonseed, corn,sunflower, arachis, castor, palm or olive oil. Preferably, the vegetableoil is soybean oil. Alternatively, the water-immiscible solvent is anester of a medium or long-chain fatty acid, for example, a mono-, di-,or triglyceride; or is a chemically modified or manufactured materialsuch as ethyl oleate, isopropyl myristate, isopropyl palmirate, aglycerol ester, polyoxyl, or hydrogenated castor oil. Thewater-immiscible solvent can also be a marine oil, for example cod liveror another fish-derived oil. Suitable solvents also include fractionatedoils, for example, fractionated coconut oil or modified soybean oil.Furthermore, the compositions of the present invention can comprise amixture of two or more of the above water-immiscible solvents.

The compositions can also comprise an emulsifier. Suitable emulsifiersinclude synthetic non-ionic emulsifiers, for example ethoxylated ethersand esters polypropylene-polyethylene block co-polymers; andphospholipids for example, naturally-occurring phospholipids, such asegg and soya phospholipids and modified or artificially manipulatedphospholipids (for example prepared by physical fractionation and/orchromatography), or mixtures thereof. Preferred emulsifiers are eggphospholipids, such as lecithin, and soya phospatides. Egg yolkphospholipids are principally composed of phosphatidylcholine andphosphatidylethanolamine. Lecithin, which is classified as aphosphatidylcholine, and which may be derived from egg yolk or soybeanoil, is another commonly used emulsifier.

The pharmaceutical formulations can also include stabilizing agents,which can alternatively be considered as co-emulsifiers. Anionicstabilizers include phosphatidylethanolamines, conjugated withpolyethylene glycol, (PEG-PE) and phosphatidylglycerols, a specificexample of which is dimyristolphosphatidylgylcerol (DMPG). Additionalexamples of useful stabilizers include oleic acid and its sodium salt,cholic acid and deoxycholic acid and their respective salts, cationiclipids such as stearylamine and oleylamine, and3β-[N-(N′,N′-dimethylaminoethane)carbamoyl]cholesterol (DC-Chol).

The pharmaceutical compositions of the invention can be made isotonicwith blood by the incorporation of a suitable tonicity modifier.Glycerol is most frequently used as a tonicity modifier. Alternativetonicity modifying agents include xylitol, mannitol, and sorbitol. Thepharmaceutical compositions are typically formulated to be atphysiologically neutral pH, typically in the range 6.0–8.5. The pH canbe adjusted by the addition of base, for example NaOH or NaHCO₃, or insome cases acid, such as HCl.

Pharmaceutically safe oil-water emulsions comprising a vegetable oil, aphosphatide emulsifier, typically egg lecithin or soybean lecithin, anda tonicity modifier are provided commercially for parenteral nutrition,for example, under the tradenames Liposyn® II and Liposyn® III (AbbottLaboratories, North Chicago, Ill.) and Intralipid® (Fresenius Kabi A B,Uppsala, Sweden.) The compounds described herein can be incorporated inthese or other similar oil-water emulsions.

A compound of the invention can also be formulated in a triglyceridecomprising esters of at least one medium chain length (C₆–C₁₂) fattyacid. Preferably the triglyceride comprises an ester of a C₈–C₁₀ fattyacid. Triglycerides suitable for formulating a compound of the inventionare provided under the tradename Miglyol® by Condea Chemie GmbH (Witten,Germany). In particular, Miglyol® 810 or 812 (caprylic (C₁₀)/capric (C₈)glyceride) are useful for formulation of the present compounds. Forexample, as detailed in Injection 11 of Example 15 below, Miglyol® 810is beneficially used as the oil phase of a formulation that includes eggyolk phosphatides as the emulsifier, DMPG as an anionic stabilizer, andglycerol as the tonicity modifier.

Additionally, the compounds described herein can be substituted forpropofol in any of the propofol compositions known to the art. Forexample, suitable sterile pharmaceutical compositions of propofol andmethods for their administration are generally described in U.S. Pat.Nos. 4,056,635; 4,452,817, 4,798,846 and 5,714,120.

Another suitable pharmaceutical composition for the administration ofpropofol, described in U.S. Pat. Nos. 6,140,373 and 6,140,374, is anoil-in-water emulsion formulation having as an antimicrobial agent, amember selected from the group consisting of benzyl alcohol; benzylalcohol and disodium ethylenediamine tetraacetate; benzyl alcohol andethylene diamine tetraacetic acid; benzethonium chloride; and benzylalcohol and sodium benzoate.

Another suitable pharmaceutical composition for the administration ofpropofol, described in U.S. Pat. Nos. 5,637,625 and 5,908,869, comprisesa sterile, pyrogen-free oil-in-water emulsion containing soybean oildispersed in water and stabilized by lecithin phospholipids, and furthercomprises an amount of edetate to inhibit the growth of gram-positiveand gram-negative bacteria.

A further suitable pharmaceutical composition for the administration ofpropofol, described in U.S. Pat. No. 5,637,625, is an oil-freeformulation in which the propofol is dispersed in water asmicro-droplets with a diameter generally less than 1 micron, having aphospholipid or monoglyceride outer covering.

Another suitable pharmaceutical composition for the administration ofpropofol, described in U.S. Pat. No. 6,100,302, consists ofphospholipid-coated microdroplets ranging from about 160 to about 200nanometers in diameter. These microdroplets contain a sphere of propofoldissolved in a solvent, such as vegetable oil, surrounded by astabilizing layer of a phospholipid, and suspended in a pharmaceuticalacceptable injectable carrier.

A further suitable pharmaceutical composition for the administration ofpropofol, described in U.S. Pat. No. 5,962,536, usesN-methylpyrrolidone, 2-pyrrolidone or other physiologically acceptableco-solvents as a solvent for the solubilization of propofol.

In yet another alternative, the present compounds can be formulatedusing a solubilizer, for example, hydroxypropyl-β-cyclodextrin, to forman inclusion complex.

In yet another alternative, the present compounds can be systemicallyadministered orally as tablets, capsules, suspensions, syrups, and thelike or as a systained-release preparation, in combination with apharmaceutically acceptable vehicle such as an inert diluent or anassimilable edible carrier. Oral pharmaceutical formulations of thepresent compounds can also include binders, excipients, a disintegratingagent, a lubricant, sweetening or flavoring agents, preservatives, orother pharmaceutically acceptable ingredients as known in thepharmaceutical arts.

Still other suitable formulations for use in the present invention canbe found in Remington's Pharmaceutical Sciences, Mace PublishingCompany, Philadelphia, Pa., 17th ed. (1985).

Compounds of the present invention can be used for the induction and/ormaintenance of general anesthesia, for example to permit the performanceof surgery or other painful procedures; for the initiation and/ormaintenance of sedation with patients spontaneously breathing, to whichthe term Monitored Anesthesia Care (MAC) sedation may be applied; andfor the induction and/or maintenance of sedation for intubated,mechanically ventilated patients.

The compounds of the invention can also be administered in combinationwith other therapeutic agents, such as, for example, other anestheticsor sedatives, or analgesics (e.g. an opioid such as the μ-opioid agonistremifentanil, fentanyl, sulfentanil, or alfentanil). Accordingly, thecompositions of the invention can optionally further comprise anothertherapeutic agent, for example, an anesthetic, sedative, or analgesic.Similarly, the therapeutic methods of the invention can also optionallycomprise administering another therapeutic agent (e.g. an anesthetic,sedative, or analgesic) to the mammal.

Alternatively, a continuous infusion of a compound of the presentinvention can be used to maintain anesthesia or sedation followinginduction with another sedative hypnotic agent. Or, in yet anotheralternative protocol, a bolus dose of the present compound to induceanesthesia or sedation can be followed by infusion of a differentsedative hypnotic agent.

The amount of an active compound required for use in treatment will varywith the route of administration and the age and condition of thepatient, and will be ultimately at the discretion of the attendantphysician or clinician.

Useful dosages of the substituted phenol compounds of the invention canbe determined by comparing their in vitro activity, and in vivo activityin animal models. Methods for the extrapolation of effective dosages inmice, and other animals, to humans are known to the art; for example,see U.S. Pat. No. 4,938,949. Such compositions and preparations shouldcontain at least 0.1% of active compound. The percentage of thecompositions and preparations can, of course, be varied and canconveniently be between about 1% to about 60% of the weight of a givenunit dosage form. The amount of active compound in such therapeuticallyuseful compositions is such that an effective dosage level will beobtained.

In general, the substituted phenol compounds of the invention can beadministered as an initial bolus induction dose followed by a continuousinfusion of the compound at a rate that is sufficient to achieve andmaintain the level of anesthesia or sedation desired. For example, asuitable bolus dose will typically be in the range of from about 0.1 toabout 50 mg/kg, preferably about 0.5 to about 20 mg/kg, and morepreferably about 1 to about 10 mg/kg. The rate of infusion willtypically be in the range from about 5 to about 2000 μg/kg/min,preferably about 10 to about 1000 μg/kg/min, and more preferably about50 to about 500 μg/kg/min. Target blood levels during infusion willtypically be, for example, in the range of from about 0.1 to about 50μg/mL, preferably about 0.5 to about 20 μg/mL, and more preferably about1.0 to about 10 μg/mL.

The in vitro stability of a compound in rat liver, skeletal muscle, andwhole blood in comparison with two clinically used esterase substrates(esmolol and remifentanil) can be determined as described in Test A.

Test A: In Vitro Stability in Rat Liver, Skeletal Muscle, and WholeBlood

Methods

Source of Enzyme

Liver and skeletal muscle tissue were harvested from rats sacrificedusing CO₂ (dry ice). Tissues were homogenized in phosphate bufferedsaline at 4° C. and 20% homogenates were prepared (on a wet weightbasis). Homogenates were aliquoted and frozen at −80° C. The totalprotein concentration in the homogenates was estimated using thebicinchoninic acid assay (Pierce). Whole blood was obtained by cardiacpuncture and collected in vacutainer tubes containing sodium heparin toprevent coagulation. Fresh blood was used in the assay and was placed inice until the time of assay.

Substrates

Esmolol was purchased as a 250 mg/mL solution (concentrated I.V. dosageform from Baxter) and diluted in sterile water to a concentration of 5mM. Remifentanil was purchased as the I.V. dosage form which was alyophilized powder. This was reconstituted in sterile water to aconcentration of 5 mM. Solutions of the substituted phenol compounds (50mM) were prepared in DMSO. All stock solutions were stored at −20° C.and their purity was established by HPLC.

Metabolism Assay

The stability of all compounds was studied at an assay concentration of100 μM. For liver and skeletal muscle, the final assay proteinconcentration was 5 mg/mL and for blood metabolism, undiluted wholeblood was used. Control incubations in the assay buffer (100 mM KH₂PO₄,pH 7.4) without any biological material were run in parallel to confirmchemical stability. The test compounds were spiked into the homogenatesor whole blood in glass tubes (0.5 mL volume) and the proteins wereimmediately precipitated with the addition of twice the volume ofice-cold ethanol and vortex mixing. This constituted the zero timepoint. In identical 0.5 mL incubations, the compounds were incubated for20 minutes at 37° C. prior to addition of the ethanol. For reactions inwhole blood, a 3 minute reaction was also performed. To all tubes, 25 μlof a 4 mg/100 mL solution of 3-acetamidophenol was added as the internalstandard and the contents were mixed by vortexing. The suspensions werecentrifuged at 14,000 rpm and the supernatants were transferred to glasstubes and evaporated under a gentle stream of nitrogen. The residue wasreconstituted in 0.2 mL of sterile water and 50 μl was analyzed by HPLC.

HPLC Method

A C₁₈, 5μ, 2×150 mm I.D (LUNA, Phenomenex) reverse-phase HPLC column wasused and a gradient from 10% to 68% acetonitrile over 15 minutesfollowed by a 5 minute isocratic run at 10% acetonitrile was used. Themobile phase components contained 0.1% TFA. The analytes were monitoredby UV detection at 214 nm.

Data Analysis

Concentrations of the substrate in incubates were measured as peak arearatios using the internal standard method and percent degradation wasmeasured relative to the zero time values.

Results

The test compounds are typically stable in the incubation buffer at 37°C. for 20 minutes. Additionally, the substituted phenol compounds testedwere found to be substrates for esterases in the rat. Typically, thesubstituted phenol compounds were completely metabolized to thecorresponding acid after a 20 minute incubation with rat liverhomogenate.

The in vitro affinity of substituted phenol compounds and theircorresponding acid metabolites for the GABA receptor can be determinedusing competitive binding assays known in the art, as described forexample in D. Sapp et al., J Pharmacol. Exp. Ther., 1992, 262, 801–807;A. Concas et al., Eur. J Pharmacol., 1994, 267, 207–213; A. Concas etal, Brain Research, 1991, 542, 225–232; and J. Hawkinson et al., Mol.Pharmacol., 1994, 46, 977–985. A suitable competitive binding assay isdescribed below in “Test B.”

Test B: In Vitro Competitive Binding Affinity Assay for the GABAReceptor

Methods

The assay was run on 100 μl scale by combining the following.

-   -   25 μl [4×] cold ligand or buffer (Tris,HCl (50 mM) with KCL (150        mM at pH 7.4)    -   25 μl [4×] [³⁵ S] TBPS at 5 nM final concentration    -   50 μl [2×] rat cortex membrane at 0.2 mg/mL final        This mixture was incubated at room temperature for 90 minutes        with shaking and filtered through a Packard 96 well GFB filter        plate soaked with 0.1% BSA. The radioactivity on the resulting        plate determined, and the ability of the test compound to        inhibit TPBS binding was calculated.        Results

Representative substituted phenol compounds were found to bind to GABAreceptors with affinities similar to propofol.

The ability of a compound to function as an anesthetic or a sedative canbe determined using assays that are known in the art (for example seeU.S. Pat. No. 5,908,869 or R. James and J. Glen, J Med Chem., 1980, 23,1350–1357) or using the assay described in Test C below.

Test C: In Vivo Assay to Measure Duration of Anesthesia

The following assay was used to determine whether the substituted phenolcompounds (and their corresponding acid derivatives) produce anesthesiaof short duration following administration via intravenous bolusadministration and infusion in rats. Rats were dosed using formulationsof from about 3 weight % to about 10 weight % active compound. Thevehicle used in the initial studies was 10% cremophor EL/90% D5W (5%dextrose in distilled water). While this vehicle proved suitable for theexperiments with bolus administration of the anesthetics, upon infusionsome toxicity was observed (i.e., lethargy and sedation). As a result,10% Liposyn III (an intravenous fat emulsion containing (per 100 mL) 10g soybean oil, ≦1.2 g egg phosphatides and 25 g glycerol) became thevehicle of choice; it produced no such adverse effects in its own rightand closely mimicked the vehicle used clinically for propofol.

Methods

Bolus Administration

Rats (adult male Sprague-Dawley) were placed in a perspex restrainer andinjected (2 mL/kg over approximately 3 seconds) with the compound ofinterest via the tail vein. The time to onset of anesthesia (defined asa loss of righting reflex), duration of anesthesia (i.e., duration ofloss of righting reflex) and behavioral recovery (i.e., duration ofataxia, sedation and/or lethargy following the return of the rightingreflex) was recorded. Duration of anesthesia was measured by placing therats ventral side uppermost following onset of anesthesia and the timeuntil recovery of the righting reflex recorded using a stopclock. Thedepth of anesthesia was assessed intermittently by observing themagnitude of the withdrawal reflex to noxious pinch of the hindpaw.Behavioral recovery was assessed by visual observation. The compoundsproduced a dose-dependent loss of righting reflex. Doses of preferredcompounds produced a 2 minute loss of righting reflex at 20 mg/kg orless.

Administration by Infusion

Rats (adult Sprague-Dawley) were placed in a perspex restrainer andanesthesia induced by bolus injection via the tail vein (1 mL/kg overapproximately 3 seconds at a dose, estimated from the earlier bolusexperiments, to produce anesthesia of approximately 2 minutes duration).Immediately after bolus administration, a 20 minute infusion, via thetail vein, was commenced (0.5 mL/kg/min at a half of the bolusdose/min). In some experiments, the initial infusion rate was maintainedthroughout, while in others, the rate was modified as necessary tomaintain a consistent depth of anesthesia (as defined by moderate pawwithdrawal in response to noxious pinch). Following completion of theinfusion, duration of anesthesia (i.e., duration of loss of rightingreflex) and behavioral recovery (i.e., duration of ataxia, sedation orlethargy following return of the righting reflex) was recorded.

Representative substituted phenol derivatives produced anesthesiafollowing bolus administration. The corresponding acids failed to induceanesthesia. Preferred compounds of this invention maintained anesthesiawhen infused i.v. at doses of 10 mg/kg/min or less and maintainedanesthesia for the duration of the i.v. infusion. Following terminationof the 20 minute infusion, recovery of the righting reflex was rapid(<10 minutes). Recovery times matched those following bolusadministration suggesting that there was little/no accumulation of thecompounds over time.

The invention will now be illustrated by the following non-limitingExamples.

EXAMPLES Example 1 4-Methoxycarbonyl-2,6-diisopropylphenol

Carbon tetrachloride (28 mL) was added dropwise to a mixture of2,6-diisopropylphenol (37.5 mL), copper powder (2 g), methanol (150 mL),and 40% aqueous solution of sodium hydroxide (150 mL), at 40–50° C. Thereaction temperature was warmed to about 60° C., and the resultingmixture was allowed to stir for 4 hours. The mixture was poured intowater and extracted with toluene (3×). The combined organics were washed(brine), dried over sodium sulfate and concentrated. Chromatography withethyl ether:hexanes as the eluent (gradient 5/95 to 8/92) providedmaterial that precipitated as a white solid upon addition of hexane. Thewhite solid was collected by filtration to provide the title compound(1.06 g); ¹H-NMR(CDCl₃) δ=1.29 (d, 12H, CH(CH₃)₂), 3.16 (m, 2H, CH(CH₃)₂), 3.87 (S, 3H, OCH₃), 5.22 (S, 1H, OH), 7.78 (S, 2H, ArH).

Example 2 (E)-4-(2-Methoxycarbonylvinyl)-2,6-diisopropylphenol

Methyl 3-(3,5-diisopropyl-4-methoxyphenyl)acrylate (610 mg) and borontribromide (10 mL) were combined in dichloromethane (10 mL) and themixture was allowed to stir at 0° C. for 5 hours. The reaction wasquenched with water and extracted with dichloromethane. The organicswere washed (brine), dried (sodium sulfate), filtered, and condensed.Chromatography, with ethyl ether:hexane (gradient 10:90 to 20:80) as theeluent, provided material that was recrystallized from hexane to givethe title compound as a white solid (420 mg); ¹H-NMR (CDCl₃) δ=1.28 (d,12H, CH(CH ₃)₂), 3.16 (m, 2H, CH(CH₃)₂), 3.80(S, 3H, OCH₃), 5.10 (S, 1H,OH), 6.32 (d, 2H, CH═CH), 7.24 (S, 2H, Ar—H), 7.66 (d, 2H, CH═CH).

The intermediate methyl 3-(3,5-diisopropyl-4-methoxyphenyl)acrylate wasprepared as follows.

a. 4-Hydroxy-3,5-diisopropylbenzaldehyde. Formaldehyde (40%, 5.0 mL) andaqueous ammonium hydroxide (30%, 3.74 mL) were added to a solution of2,6-diisopropylphenol (5.0 g) in glacial acetic acid (270 mL). After 24hours on a stream bath, the solvents were evaporated under reducedpressure. The resulting material was dissolved in chloroform, washedwith 5% aqueous sodium bicarbonate, dried (MgSO₄), filtered, andconcentrated. Chromatography, with 10% ethyl acetate in hexanes as theeluent, provided the aldehyde (520 mg).

b. 3,5-diisopropyl-4-methoxybenzaldehyde.4-Hydroxy-3,5-diisopropylbenzaldehyde (1.36 g), iodomethane (0.5 mL),and potassium carbonate (1.85 g) were combined in a solution of acetone(40 mL) and dimethyl formamide (10 mL). The reaction mixture was stirredat room temperature for 24 hours and concentrated. The resultingmaterial was taken into diethyl ether, washed (brine), dried (sodiumsulfate), filtered, and concentrated to give the methyl ether as ayellow oil (1.4 g).

c. Methyl 3-(3,5-diisopropyl-4-methoxyphenyl)acrylate.3,5-diisopropyl-4-methoxybenzaldehyde (881 mg) free powder.Ph₃P═CHCOOCH₃ (1.7 g) was added, followed by 10 mL of hexane. Thereaction mixture was heated at 50° C. for 24 hours, and the resultingmixture was loaded on a silica-gel column. Chromatography, with diethylether:hexane (10:90) as the eluent, provided the ester (944 mg).

Example 3 2,6-Diisopropyl-4-methoxycarbonylmethylphenol

To a solution of methyl 3,5-diisopropyl-4-methoxyphenylacetate (100 mg)in dichloromethane (12 mL) at −78° C. was added a solution of borontribromide (0.57 mL) in dichloromethane. The reaction mixture wasstirred at −78° C. for 1 hour and at 0° C. for 1 hour, quenched bywater, and extracted with dichloromethane. The combined organics werewashed (brine), dried (MgSO₄), filtered, and concentrated. Purificationby preparative thin layer chromatography, with ethylacetate:hexane:acetic acid (90:9:1) gave the title compound (24 mg);¹H-NMR (CDCl₃) δ=1.25 (d, 12H, CH(CH₃ )₂), 3.15 (m, 2H, CCH(CH₃)₂), 3.55(S, 2H, CH₂), 3.70 (S, 3H, OCH₃), 6.98 (S, 2H, ArH)

The intermediate methyl 3,5-diisopropyl-4-methoxyphenylacetate wasprepared as follows.

a. 2,6-Diisopropyl-1-(2-propenyloxy)benzene. 2,6-diisopropylphenol (12g) was dissolved in dimethylformamide (200 mL) and sodium hydride (5.4g) was added. The mixture was stirred at 0° C. for 5 minutes and atambient temperature for another 15 minutes. The solution was cooled to0° C., allyl iodide (9.3 mL) was added, and the mixture was stirred atfor 15 minutes. The mixture was allowed to warm to ambient temperatureand was stirred for another 2 hours. Saturated aqueous ammonium chloridewas added and the mixture was extracted with ethyl acetate. The combinedorganics were dried (MgSO₄), filtered through a pad of silica gel, andconcentrated to provide the ether (16 g).

b. 4-Allyl-2.6-diisopropylphenol.2,6-Diisopropyl-1-(2-propenyloxy)benzene (1.5 g) andN,N-dimethylpropyleneurea (14 mL) were combined and heated to 165° C. ina sealed tube for 4 hours. The reaction mixture was poured into etherand the ether was washed with water, dried (sodium sulfate), filteredand condensed. Chromatography with ether:hexanes (gradient 2:98 to 5:98)provided the phenol, which was used without further purification.

c. 4-Allyl-2,6-diisopropyl-1-methoxybenzene.4-Allyl-2,6-diisopropylphenol (9.2 g) and potassium carbonate (0.7 g)were combined in dimethylformamide (60 mL) and iodomethane (3.2 mL) wasadded. After 2 hours, additional potassium carbonate (2 g) andiodomethane (1 mL) were added. After 12 hours, the reaction mixture waspartitioned between ethyl acetate and water. The organic phase waswashed with saturated aqueous sodium bicarbonate and brine, dried(MgSO₄), filtered through a thin pad of silica gel, and concentrated togive the methyl ether as a light yellow oil (10.7 g).

d. 4-Carboxymethyl-2,6-diisopropyl-1-methoxybenzene.

Benzyltriethylammonium bromide (360 mg) and potassium permanganate (2.6g) were added to a solution of 4-allyl-2,6-diisopropyl-1-methoxybenzene(1.5 g) at 0° C. The reaction mixture was stirred vigorously for 1 hourand was warmed to 10° C. and stirred for an additional hour. A 5%solution of Na₂S₂O₅ in water was added, followed by 1 N HCl to make themixture acidic. The mixture was washed twice with dichloromethane andthe combined organics were dried (MgSO₄), filtered, and concentrated.Chromatography, with 10% ethyl acetate in hexanes (with acetic acid) asthe eluent, provided the acid.

e. 3,5-Diisopropyl-4-methoxyphenylacetate.4-Carboxymethyl-2,6-diisopropyl-1-methoxybenzene (200 mg) was combinedwith 2 drops concentrated sulfuric acid in methanol (2.5 mL) and themixture was heated to 80° C. for 2 hours. The mixture was concentratedand purified by chromatography with 5% EtOAc in hexanes (with 1% aceticacid) as the eluent, to provide the methyl ester (100 mg).

Example 4 4-(2-Methoxycarbonylethyl)-2,6-diisopropylphenol

4-(2-Methoxycarbonylvinyl)-2,6-diisopropylphenol (Example 1, 350 mg) wasdissolved in a solution of ethyl acetate (10 mL) and methanol (10 mL)and hydrogenated at 35 psi over palladium on carbon (Pd/C) for 24 hours.The resulting mixture was filtered and the filtrate was concentrated toprovide the title compound; ¹H-NMR (CDCl₃) δ=1.27 (d, 12H, CH(CH₂ )₂),2.60 (t, 2H, CH₂), 2.87 (t, 2H, CH₂), 3.13 (m, 2H, CH(CH₃)₂), 3.68(S,3H, OCH₃), 6.87 (S, 2H, ArH).

Example 5 7-isopropyl-2-methyl-benzofuran-3-one

2-isopropylphenol (10 mL) was dissolved in anhydrous methylene chloride(150 mL), methyl pyruvate (7.3 mL) was added and the solution was cooledin an ice bath and flushed with nitrogen. A 1.0 M solution of titanium(IV) chloride in methylene chloride (72 mL) was added dropwise over 1hour via addition funnel while still under nitrogen. The reaction wasstirred for another 1 hour after completion of addition until reactionwas complete.

The mixture was then poured into a suspension of zinc (0) (20 g) in asolution of acetic acid (50 mL) and methylene chloride (100 mL). Thismixture was then heated slowly to 90° C. and the methylene chloride wasdistilled off, the mixture was heated for another 30 minutes afterdistillation was finished and reaction was complete.

Once cooled, the mixture was decanted into ether (400 mL) and washedwith distilled water (4×200 mL). The organic was collected andneutralized with saturated sodium bicarbonate solution to neutral pH,then washed with brine (1×) and dried over magnesium sulphate, andconcentrated under vacuum yielding crude product (12.7 g).

Chromatography with 5% ethyl acetate:hexanes as the eluent provided acolourless oil of 7-isopropyl-2-methyl-benzofuran-3-one (10.7 g).(Intermediate (A), wherein R₅ and R₄=methyl). ¹H-NMR(DMSO) δ=1.15 (d ofd, 6H, CH₃(i-Pr)), 1.35 (d, 3H, CH₃), 3.00 (m, 1H, CH(i-Pr)), 3.90 (q,1H, CH), 7.04 (t, 1H, ArH), 7.14 (d, 2H, ArH).

Example 6 7-sec-butyl-2-methyl-benzofuran-3-one

Using the procedure described in Example 5, substituting2-sec-butylphenol (10 mL) for 2-isopropylphenol as the startingmaterial, a colourless oil of intermediate7-sec-butyl-2-methyl-benzofuran-3-one was synthesized. (Intermediate(A), wherein R₅=ethyl; R₄=methyl). ¹H-NMR(DMSO) δ=0.65 (t, 3H, CH₃),1.02 (d, 3H, CH₃), 1.43 (d, 3H, CH₃), 1.59 (m, 2H, CH₂), 2.75 (m, 1H,CH(sec)), 3.97 (m, 1H, CH), 7.00–7.20 (m, 3H, ArH).

Example 7 2-ethyl-7-isopropyl-benzofuran-3-one

Using the procedure described in Example 5, substituting reagent methyl2-ketobutyrate (8.0 mL) for methyl pyruvate, provided a colourless oilof 2-ethyl-7-isopropyl-benzofuran-3-one. (Intermediate (A), whereinR₅=methyl; R₄=ethyl). ¹H-NMR(DMSO δ=0.75 (t, 3H, CH₃), 1.14 (d of d, 6H,CH₃(i-Pr)), 1.87 (m, 2H, CH₂), 3.00 (m, 1H, CH(i-Pr)), 3.90 (t, 1H, CH),7.05 (t, 1H, ArH), 7.14 (d, 2H, ArH).

Example 8 7-sec-butyl-2-ethyl-benzofuran-3-one

Using the procedure described in Example 6, substituting reagent methyl2-ketobutyrate (8.0 mL) for methyl pyruvate, a colourless oil ofintermediate 7-sec-butyl-2-ethyl-benzofuran-3-one was obtained.(Intermediate (A), wherein R₅=ethyl; R₄=ethyl).

Example 9

(a) 6-isopropyl-2-(1-ethoxycarbonylethyl)-phenol

7-isopropyl-2-methyl-benzofuran-3-one, synthesized in Example 5, (3.8 g)was dissolved in anhydrous ethanol (200 mL) and cooled in an ice bathunder nitrogen before addition of titanium (IV) isopropoxide (6.25 mL).The reaction was then heated to 90° C. for a few hours. Once cooled, thereaction mixture was poured into hexanes and washed with saturatedammonium chloride solution, brine, dried over magnesium sulphate andconcentrated under vacuum. Chromatography with 2% ethyl acetate:hexanesas the eluent provided a colourless oil of6-isopropyl-2-(1-ethoxycarbonylethyl)-phenol, alternatively known as2-(2-hydroxy-3-isopropyl-phenyl)-propionic acid ethyl ester. (A compoundof formula (X) wherein R₅ and R₄=methyl; R_(a)=ethyl). (¹H-NMR(DMSO)δ=1.02 (m, 9H, CH₃), 1.22 (d, 3H, CH₃), 3.19 (m, 1H, CH), 3.95 (m, 3H,CH+CH₂O), 6.68 (t, 1H, ArH), 6.81 (d, 1H, ArH), 6.98 (d, 1H, ArH), 8.28(s, 1H, Ar—OH).

(b) 6-isopropyl-2-(1-propoxycarbonylethyl)-phenol, alternatively knownas 2-(2-hydroxy-3-isopropyl-phenyl)-propionic acid propyl ester, isobtained by substituting anhydrous propanol for ethanol using theprocedure described in Example 9(a) above. (A compound of formula (X)wherein R₅ and R₄=methyl; R_(a)=propyl).(c) 6-isopropyl-2-(2-propoxycarbonylethyl)-phenol, alternatively knownas 2-(2-hydroxy-3-isopropyl-phenyl)-propionic acid isopropyl ester, isobtained by using the procedure described in Example 9(a) above, andsubstituting anhydrous iso-propanol for ethanol. (A compound of formula(X) wherein R₅ and R₄=methyl; R_(a)=isopropyl).

Example 10 6-(2-sec-butyl)-2-(1-ethoxycarbonylethyl)-phenol

Using the procedure described in Example 9(a) above, and starting with7-sec-butyl-2-methyl-benzofuran-3-one, synthesized in Example 6, acolourless oil of the title compound, alternatively known as2-(3-sec-butyl-2-hydroxy-phenyl)-propionic acid ethyl ester, wasobtained. (A compound of formula (X) wherein R₅=ethyl; R₄=methyl;R_(a)=ethyl). ¹H-NMR(DMSO) δ=0.70 (q, 3H, CH₃), 1.02 (m, 6H, CH₃), 1.22(d, 3H, CH₃), 1,41 (m, 2H, CH₂), 3.00 (q, 1H, CH), 3.95 (m, 3H,CH+CH₂O), 6.68 (t, 1H, ArH), 6.81 (d, 1H, ArH), 6.95 (d, 1H, ArH), 8.25(s, 1H, Ar—OH).

Example 11 6-isopropyl-2-(1-ethoxycarbonylpropyl)-phenol

Using the method described in Example 9(a) above, and starting with2-ethyl-7-isopropyl-benzofuran-3-one synthesized in Example 7, acolorlous oil of the title compound, alternatively known as3-(2-hydroxy-3-isopropyl-phenyl)-butyric acid ethyl ester, was obtained.(A compound of formula (X) wherein R₅=methyl; R₄=ethyl; R_(a)=ethyl).

Example 12 6-isopropyl-2-(1-ethoxycarbonyl-1-hydroxyethyl)-phenol

2-isopropylphenol (10 mL) was dissolved in anhydrous methylene chloride(150 mL); ethyl pyruvate (8.3 mL) was added and the solution was cooledin an ice bath and flushed with nitrogen. A solution of titanium (IV)chloride (8.2 mL) in methylene chloride (˜75 mL) was prepared and addeddropwise over 1 hour via addition funnel while still under nitrogen. Thereaction was stirred for another 1–2 hours after completion of additionuntil reaction was complete. The mixture was diluted with ether (400 mL)and washed with distilled water (4×200 mL), brine (1×), dried overmagnesium sulphate, and concentrated under vacuum yielding a yellow oilas crude product of the title compound, alternatively known as2-hydroxy-2-(2-hydroxy-3-isopropyl-phenyl)-propionic acid ethyl ester(18.9 g). (Intermediate (B) where R₅=R₄=methyl and R_(a)=ethyl).¹H-NMR(DMSO) δ=0.99–1.06 (m, 9H, CH₃), 1.59 (s, 3H, CH₃), 3.15 (m, 1H,CH(i-Pr)), 3.99 (m, 2H, CH₂O), 6.72 (t, 1H, ArH), 7.00 (d, 2H, ArH),9.03(s, 1H, ArOH).

Using the procedure described above and substituting 2-sec-butylphenolfor 2-isopropylphenol,6-(2-sec-butyl)-2-(1-ethoxycarbonyl-1-hydroxyethyl)-phenol (Intermediate(B) where R₅=ethyl; R₄=methyl and R_(a)=ethyl) is obtained.

Using the procedure described above and substitutingmethyl-2-ketobutyrate for ethyl pyruvate,6-isopropyl-2-(1-ethoxycarbonyl-1-hydroxypropyl)-phenol (Intermediate(B) wherein R₅=methyl; R₄=ethyl and R_(a)=ethyl) is obtained.

Example 13 6-isopropyl-2-(1-ethoxycarbonylethyl)-phenol

6-isopropyl-2-(1-ethoxycarbonyl-1-hydroxyethyl)-phenol, synthesized inExample 12, (18.9 g) was dissolved in anhydrous methylene chloride (250mL) and cooled in an ice bath under nitrogen before addition of pyridine(36 mL). Acetic anhydride (28 mL) was then added and the reactionstirred overnight while slowly warming to room temperature. The solutionwas diluted with diethyl ether and washed with saturated ammoniumchloride solution, 1N HCl, brine, dried over magnesium sulphate andconcentrated under vacuum to give a yellow oil as crude productmaterial.

The crude product material was dissolved in methanol (250 mL), 10% Pd/C(2.1 g) wet with distilled water; and methanol was added and the mixturewas hydrogenated overnight at 30 psi hydrogen with shaking. The Pd/C wasremoved by filtration and rinsed with methanol and solvent was removedunder vacuum yielding a yellow oil as crude product (19 g).

Chromatography of the crude product with 1% ethyl acetate:hexanes as theeluent provided a light yellow oil of the title compound, alternativelyknown as 2-(2-hydroxy-3-isopropyl-phenyl)-propionic acid ethyl ester(3.8 g). (A compound of formula (X) wherein R₅═R₄=methyl andR_(a)=ethyl). ¹H-NMR(DMSO) δ=1.02–1.07 (m, 9H, CH₃), 1.23 (d, 3H, CH₃),3.20 (m, 1H, CH₃(i-Pr)), 3.97 (m, 3H, CH, CH₂O), 6.72 (t, 1H, ArH), 6.81(d, 1H, ArH), 6.96 (d, 1H, ArH), 8.28 (s, 1H, ArOH).

Example 14

Following the procedures described in Examples 5–13, the followingcompounds of formula (X) can be prepared.

TABLE I R₅ R₄ R_(a) Compound ethyl methyl propyl 6-(2-sec-butyl)-2-(1-propoxycarbonylethyl)-phenol ethyl methyl isopropyl6-(2-sec-butyl)-2- (2-propoxycarbonylethyl)-phenol methyl ethyl propyl6-isopropyl-2-(1- propoxycarbonylpropyl)-phenol methyl ethyl isopropyl6-isopropyl-2- (2-propoxycarbonylpropyl)-phenol ethyl ethyl ethyl6-(2-sec-butyl)-2- (1-ethoxycarbonylpropyl)-phenol ethyl ethyl propyl6-(2-sec-butyl)-2-(1- propoxycarbonylpropyl)-phenol ethyl ethylisopropyl 6-(2-sec-butyl)-2- (2-propoxycarbonylpropyl)-phenol

Example 15

The following illustrates representative pharmaceutical dosage forms,containing a substituted phenol ring linked to a reactive functionalgroup (‘Active Compound’), for therapeutic or prophylactic use in humansand animals.

(i) Injection 1 wt % ‘Active Compound’ 2.0 soybean oil 10.0 eggphosphatide 1.2 glycerol 2.25 disodium edetate dihydrate 0.0055 sodiumhydroxide q.s. water for injection to 100 (ii) Injection 2 wt % ‘ActiveCompound’ 1.0 soybean oil 5.0 fractionated coconut oil 5.0 eggphosphatide 1.2 glycerol 2.25 disodium edetate dihydrate 0.0055 sodiumhydroxide q.s. water for injection to 100 (iii) Injection 3 ‘ActiveCompound’ 1.0% w/v N-methylpyrrolidinone 30% w/v propylene glycol 40%w/v water for injection to 100 (iv) Injection 4 ‘Active Compound’ 2.0%w/v N-methylpyrrolidinone 30% w/v propylene glycol 40% w/v water forinjection to 100 (v) Injection 5 wt % ‘Active Compound’ 1.0 soybean oil1.0–3.0 lecithin 1.2 glycerol 2.25 sodium hydroxide q.s. water forinjection to 100 (vi) Injection 6 wt % ‘Active Compound’ 1.0% w/vsoybean oil 10.0% w/v safflower oil 10.0% w/v egg phosphatids 1.2% w/vglycerol 2.5% w/v sodium hydroxide q.s. water to 100 (vii) Injection 7‘Active Compound’ 1.0% w/v soybean oil 10.0% w/v egg phosphatids 1.2%w/v glycerol 2.5% w/v sodium hydroxide q.s. water for injection to 100(viii) Injection 8 ‘Active Compound’ 1.0% w/v soybean oil 30.0% w/vphosphatidylcholine 1.2% w/v from egg yolk glycerol 1.67% w/v sodiumhydroxide q.s. water for injection to 100 (ix) Injection 9 wt % ‘ActiveCompound’ 10.0% w/v caprylic/capric triglyceride 10.0% w/v eggphosphatides 1.2% w/v glycerol 2.5% w/v sodium hydroxide q.s. water to100 (x) Injection 10 wt % ‘Active Compound’ 5.0% w/v caprylic/caprictriglyceride 15.0% w/v egg phosphatides 1.2% w/v glycerol 2.5% w/vsodium hydroxide q.s. water to 100 (xi) Injection 11 wt % ‘ActiveCompound’ 10% w/v Miglyol ® 810 5.0–10.0% w/v egg yolk phosphatides0.5–1.0% w/v DMPG 0.1% w/v glycerol 2.25% w/v sodium hydroxide q.s.water to 100 (xii) Injection 12 wt % ‘Active Compound’ 5% w/vMiglyol ® 810 20% w/v egg yolk phosphatides 0.5–1.0% w/v glycerol 2.25%w/v sodium hydroxide q.s. water to 100 (xiii) Injection 13 wt % ‘ActiveCompound’ 4.0–10.0% w/v vegetable oil 0.5–20.0% w/v egg yolkphosphatides 0.5–1.2% w/v glycerol 0.5–2.5% w/v sodium hydroxide q.s.water to 100

The above formulations can be obtained by conventional procedures wellknown in the pharmaceutical art.

All publications, patents, and patent documents are incorporated byreference herein, as though individually incorporated by reference. Theinvention has been described with reference to various specific andpreferred embodiments and techniques. However, it should be understoodthat many variations and modifications may be made while remainingwithin the spirit and scope of the invention.

1. A method of inducing or maintaining anesthesia or sedation in amammal by administering an effective amount of a substituted phenolanesthetic agent, wherein the improvement comprises: administering tothe mammal an effective amount of a substituted phenol anesthetic agentcontaining a reactive functional group, wherein the reactive functionalgroup is bonded to the substituted phenol anesthetic agent by a linkercontaining from 1 to 12 carbon atoms and wherein the reactive functionalgroup is converted in vivo into a functional group which renders theresulting compound inactive as an anesthetic agent.
 2. The method ofclaim 1, wherein the reactive functional group is selected from acarboxylic acid ester, a carboxylic acid thioester, a phosphonic acidester, a phosphonic acid thioester, and a carboxylic anhydride.
 3. Themethod of claim 2, wherein the reactive functional group is converted invivo to provide the corresponding carboxylic acid or phosphonic acid. 4.The method of claim 3, wherein the reactive functional group is selectedfrom —C(═O)OR_(a), —C(═O)SR_(a), —P(═O)(OR_(a))₂,—C(═O)OCH₂C(═O)N(R_(a))₂, and —C(═O)OC(═O)R_(a); wherein each R_(a) isindependently selected from a hydrocarbyl group containing from 1 to 20carbon atoms and optionally containing from 1 to 5 heteroatoms selectedfrom the group consisting of halo, nitrogen, oxygen and sulfur.
 5. Themethod of claim 4, wherein the reactive functional group is—C(═O)OR_(a).
 6. The method of claim 4, wherein R_(a) is selected fromthe group consisting of (C₁–C₈)alkyl, (C₂–C₈)alkenyl, (C₂–C₈)alkynyl,(C₃–C₈)cycloalkyl, (C₃–C₈)cycloalkyl (C₃–C₈)cycloalkyl(C₁–C₈)alkyl,(C₃–C₈)cycloalkenyl(C₁–C₈)alkyl, aryl, aryl (C₁–C₈)alkyl,aryl(C₁–C₈)alkenyl, and aryl(C₁–C₈)alkynyl, wherein any (C₁–C₈)alkyl,(C₁–C₈)alkenyl, (C₁–C₈)alkynyl, (₃–C₈)cycloalkyl, or aryl is optionallysubstituted by one or more substituents independently selected from thegroup consisting of halo, cyano, (C₁–C₈)alkoxycarbonyl, (C₁–C₈)alkanoyl,and (C₁–C₈)alkoxy.
 7. The method of claim 1, wherein the substitutedphenol anesthetic is a compound of formula (I):

wherein R₁ is (C₁–C₈)alkyl, (C₃–C₈)cycloalkyl, or(C₃–C₈)cycloalkyl(C₁–C₈)alkyl; L is a hydrocarbylene group containingfrom 1 to 12 carbon atoms and optionally containing from 1 to 5heteroatoms selected from the group consisting of oxygen, nitrogen, andsulfur; and R₃ is selected from the group consisting of —C(═O)OR_(a),—C(═O)SR_(a), —P(═O)(OR_(a))₂, —C(═O)OCH₂C(═O)N(R_(a))₂, and—C(═O)OC(═O)R_(a) wherein each R_(a) is independently selected from ahydrocarbyl group containing from 1 to 20 carbon atoms and optionallycontaining from 1 to 5 heteroatoms selected from the group consisting ofhalo, nitrogen, oxygen and sulfur; or a pharmaceutically acceptable saltthereof.
 8. The method of claim 1, wherein the substituted phenolanesthetic is a compound of formula (II):

wherein R₁ and R₂ are each independently (C₁–C₈)alkyl,(C₃–C₈)cycloalkyl, or (C₃–C₈)cycloalkyl(C₁–C₈)alkyl; L is selected fromthe group consisting of a covalent bond, and a hydrocarbylene groupcontaining from 1 to 12 carbon atoms and optionally containing from 1 to5 heteroatoms selected from the group consisting of oxygen, nitrogen,and sulfur; and R₃ is selected from the group consisting of—C(═O)OR_(a), —C(═O)SR_(a), —P(═O)(OR_(a))₂, —C(═O)OCH₂C(═O)N(R_(a))₂,and —C(═O)OC(═O)R_(a) wherein each R_(a)is independently selected from ahydrocarbyl group containing from 1 to 20 carbon atoms and optionallycontaining from 1 to 5 heteroatoms selected from the group consisting ofhalo, nitrogen, oxygen and sulfur; or a pharmaceutically acceptable saltthereof.
 9. The method of claim 7 wherein L is methylene, ethylene,vinylene, propylene, allylene, butylene, pentylene, or hexylene.
 10. Themethod of claim 9 wherein R_(a) is (C₂–C₈)alkyl, (C₂–C₈)alkenyl,(C₂–C₈)alkynyl, (C₃–C₈)cycloalkyl, aryl, aryl(C₁–C₈)alkyl,aryl(C₁–C₈)alkenyl, or aryl(C₁–C₈)alkynyl.